Effects of Sequential Anti-Resorptive Agents on Bone Mineral Density Following Denosumab Withdrawal: A Multicenter Real-World Study in Korea (MAXCARE Study)

Jeonghoon Ha; Kyong Yeun Jung; Kyoung Jin Kim; Seong Hee Ahn; Hyo-Jeong Kim; Yoon-Sok Chung

doi:10.3803/EnM.2024.2227

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Original Article Effects of Sequential Anti-Resorptive Agents on Bone Mineral Density Following Denosumab Withdrawal: A Multicenter Real-World Study in Korea (MAXCARE Study): Jeonghoon Ha^1,2*, Kyong Yeun Jung^3*, Kyoung Jin Kim⁴, Seong Hee Ahn⁵, Hyo-Jeong Kim³, Yoon-Sok Chung^6,7, on Behalf of MAXCARE Research Group; DOI: https://doi.org/10.3803/EnM.2024.2227
Published online: February 11, 2025

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

²Division of Endocrinology, Stanford University School of Medicine, Stanford, CA, USA

³Division of Endocrinology and Metabolism, Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University, Seoul, Korea

⁴Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

⁵Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Korea

⁶Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea

⁷Institute on Aging, Ajou University Medical Center, Suwon, Korea

Corresponding authors: Yoon-Sok Chung. Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea Tel: +82-31-219-5127, Fax: +82-31-219-4497, E-mail: yschung@ajou.ac.kr

Hyo-Jeong Kim. Division of Endocrinology and Metabolism, Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University, 68 Hangeulbiseong-ro, Nowongu, Seoul 01830, Korea Tel: +82-2-970-8558, Fax: +82-2-971-8212, E-mail: kimhj@eulji.ac.kr

*These authors contributed equally to this work.

• Received: October 31, 2024 • Revised: December 13, 2024 • Accepted: January 13, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
Article information
References

ABSTRACT

Background
Denosumab is a potent anti-resorptive agent widely used for osteoporosis. However, its discontinuation results in a ‘rebound phenomenon’ of rapid bone loss, necessitating transition to alternative anti-resorptive therapies. Despite this, there is limited evidence to guide the selection of the most effective agent, particularly among bisphosphonates. This study aimed to evaluate the efficacy of different anti-resorptive therapies following denosumab discontinuation in a real-world clinical setting.
Methods
This retrospective study included 360 patients (low-dose alendronate/calcitriol combination [MXM, n=118], alendronate [ALD, n=53], risedronate [RIS, n=20], ibandronate [IBN, n=30], zoledronic acid [ZOL, n=106], selective estrogen receptor modulator [SERM, n=33]) who received at least 12 months of post-denosumab anti-resorptive therapy. Bone mineral density (BMD) changes from baseline and fracture patterns were assessed over the treatment period.
Results
Baseline characteristics, including age and body mass index, were comparable across groups, with an average of 4.2 denosumab administrations per patient. The SERM group experienced the greatest BMD decline across all sites. Significant BMD reductions in the lumbar spine and femoral neck and in the femoral neck alone were observed in the IBN and RIS groups, respectively. While BMD decline was also observed in the MXM, ALD, and ZOL groups, these changes were not statistically significant.
Conclusion
MXM, ALD, and ZOL mitigated BMD loss following denosumab discontinuation. Conversely, RIS, IBN, and SERM did not adequately prevent BMD decline. These findings underscore the importance of selecting the most appropriate sequential antiresorptive therapy in clinical practice to minimize BMD loss and reduce the risk of adverse outcomes.
Keywords: Denosumab; Diphosphonates; Selective estrogen receptor modulators; Osteoporosis; Bone density

INTRODUCTION

Osteoporosis, a chronic bone disorder characterized by reduced bone mass and weakened bone architecture, significantly increases the risk of fractures, especially in older adults [1]. The primary goal of osteoporosis treatment is to improve bone mineral density (BMD) and reduce fracture risk, which is associated with significant morbidities, mortalities, and healthcare costs [2]. However, given the growing population age, the management of osteoporotic fractures has become a major public health concern [2].

Denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor-kappa B ligand (RANKL), has emerged as a highly effective treatment for osteoporosis. By inhibiting osteoclast activity, denosumab reduces bone resorption and increases BMD [3]. Clinical trials have demonstrated its efficacy in significantly preventing vertebral, nonvertebral, and hip fractures [3,4], leading to its widespread recommendation in various clinical guidelines, particularly for postmenopausal women and individuals at high to very high fracture risk [5-11]. Moreover, studies show that these benefits are maintained for up to 10 years, with expectations of further BMD improvement beyond this period [12,13]. Despite this, a major concern associated with denosumab therapy is the potential for skeletal complications following its discontinuation [14]. Unlike bisphosphonates, the effects of denosumab are reversible, resulting in rapid BMD loss and an elevated risk of multiple vertebral fractures [12,15,16]. This ‘rebound phenomenon’ highlights the importance of meticulous transition to alternative anti-resorptive agents following denosumab discontinuation [12,17].

Zoledronic acid (ZOL), an intravenous bisphosphonate, is widely utilized as a follow-up treatment after denosumab administration, particularly in long-term users [17]. Clinical evidence supports its timely administration post-denosumab treatment for the risk reduction of vertebral fractures [17-21]. Nevertheless, ZOL may not be suitable for all patients, such as those with contraindications. Alternative bisphosphonates should be considered for these cases, although their efficacy in maintaining BMD or preventing fractures post-denosumab is less established [18]. The scarcity of real-world comparative studies among different agents further complicates clinical decision-making.

To address these gaps, a multicenter retrospective analysis utilizing real-world clinical data from five university hospitals in Korea was conducted to evaluate the efficacy of various anti-resorptive agents in preventing BMD loss and fractures following denosumab discontinuation. This study aimed to provide valuable insights for clinicians to optimize the management of patients transitioning from denosumab therapy.

Study design and population: This retrospective observational study was conducted at five university hospitals in Korea. A total of 360 postmenopausal patients with osteoporosis who transitioned to alternative anti-resorptive therapies following denosumab discontinuation were analyzed. All patients had received at least two injections of denosumab (60 mg subcutaneously every 6 months) and were switched to one of several anti-resorptive agents: low-dose alendronate/calcitriol (MXM, n=118), alendronate (ALD, n=53), risedronate (RIS, n=20), ibandronate (IBN, n=30), ZOL (n=106), or selective estrogen receptor modulator (SERM, n=33). The transition was facilitated immediately 6 months after the last denosumab dose. Follow-up treatment initiation was defined as the baseline, and subsequent changes in BMD and fracture occurrences were evaluated over the treatment period (Fig. 1).; Low-dose ALD consists of 5 mg of ALD (a total of 35 mg per week) and 0.5 μg of calcitriol daily. ALD was given as a 70-mg weekly oral formulation, RIS was administered 35 mg weekly, and IBN was given either as a 3-mg injection every 3 months or a 150-mg oral dose once monthly. SERM included daily oral doses of raloxifene (60 mg) or bazedoxifene (20 mg). All therapies were administered for at least 12 months. Patients with conditions that could influence BMD or bone metabolism were excluded, such as severe renal impairment (glomerular filtration rate [GFR] <30 mL/min/1.73 m²), liver cirrhosis, recent malignancy (within the last 5 years), undergoing active cancer treatment, uncontrolled hyperparathyroidism or hyperthyroidism, osteomalacia, Paget’s disease, and other metabolic bone disorders. Patients receiving medications that can affect BMD or bone metabolism, including glucocorticoids, immunosuppressants, aromatase inhibitors, anticonvulsants, antidepressants, antiviral agents for human immunodeficiency diseases or liver diseases, thiazolidinediones, gondadotrophin releasing hormones, or anticoagulants were also excluded. All participants were advised to maintain adequate calcium intake (1,000 mg/day), vitamin D supplementation (≥800 IU/day), with serum 25-hydroxyvitamin D (25(OH)D) levels monitored to ensure they remained at or above 30 ng/mL, and to engage in at least 150 minutes of exercise per week, as recommended in standard clinical practice. BMD was measured at the start of denosumab treatment, 6 months after the final denosumab dose prior to transitioning (baseline), and at 12 and 24 months following exclusive anti-resorptive agent therapy. The primary outcome was BMD changes (%) at each site after 12 months of therapy. Secondary outcomes included BMD changes after 24 months, fracture incidence and patterns during follow-up treatment, and serum calcium alterations throughout the study period.; This study was approved by the Institutional Review Boards of the participating institutions: The Catholic University of Korea (KC24WISI0280), Eulji University School of Medicine (2024-02-014), Korea University College of Medicine (2024A N0038), Inha University College of Medicine (2023-12-016), and Ajou University Medical Center (AJOUIRB-DB-2024-138). Written informed consent by the patients was waived due to a retrospective nature of our study.
BMD measurement: BMD values (g/cm²) of the lumbar spine, femoral neck, and total hip were measured using dual-energy X-ray absorptiometry (DXA). Instruments were calibrated using a device-specific lumbar phantom, following the manufacturer’s guidelines. In this study, HOLOGIC (Marlborough, MA, USA) and GE (Cambridge, MA, USA) densitometers were employed, and validated conversion formulas were applied to standardize BMD values to HOLOGIC-equivalent measurements, minimizing inter-device variability [22,23]. BMD changes were reported as mean±standard deviation (SD) with percentage changes. Measurements were classified based on the lowest T-score at each site as follows: normal BMD (T-score ≥−1.0), osteopenia (−1.0< T-score <−2.5), and osteoporosis (T-score ≤−2.5). To ensure accurate measurements, quality control of the DXA equipment was performed at each institution, according to the manufacturer’s protocol.
Other measurements: Serum calcium, phosphorus, albumin, and creatinine levels were measured using an autoanalyzer, whereas 25(OH)D levels were assessed using immunoassay analyzers at each institution. Serum concentrations of crosslinked C-telopeptide of type I collagen (CTx) (Elecsys B-CrossLaps, Roche Diagnostics, Rotkreuz, Switzerland) were measured using an electrochemiluminescence immunoassay analyzer. GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. All serum samples were collected in the morning following an 8-hour fasting period at each visit. Since blood test timing varies in real-world clinical practice, measurements taken within a 6-month window before or after the scheduled assessment were deemed acceptable for analysis. During BMD assessments, the height and weight of each patient was recorded, and body mass index (BMI) was calculated using the formula: weight (kg)/height (m)². Vertebral fractures were assessed radiologically, as confirmed by experienced radiologists. Other fractures were identified based on patient or radiological information obtained during the clinical course.
Statistical analysis: Data were presented as mean±SD, unless otherwise specified. Graphical representations were generated using GraphPad Prism version 10.0 (GraphPad Software Inc., San Diego, CA, USA). Categorical variables were analyzed using the chi-square test, while continuous variables were assessed using analysis of variance (ANOVA) or analysis of covariance (ANCOVA), when appropriate. Mean percentage changes from baseline BMD and biochemical markers were evaluated using repeated measures with Dunnett’s multiple comparison test. All statistical analyses were performed using SPSS version 29.0 for Windows (IBM Corp., Armonk, NY, USA), and statistical significance was set at P value <0.05.

Baseline characteristics: Baseline characteristics of the study population at the initiation of sequential post-denosumab therapy are summarized in Table 1. A total of 360 patients were included and distributed as follows: MXM (n=118), ALD (n=53), RIS (n=20), IBN (n=30), ZOL (n=106), and SERM (n=33). The mean age was 67.4±8.8 years, ranging from 65.8 to 69.0 years, with no significant differences across groups (P=0.198). The majority of the study population was female (92.7%), without significant variation across groups (P=0.152). The mean BMI ranged from 22.0 to 24.2 kg/m², showing no significant differences among groups (P=0.116). In contrast, the prevalence of prior fractures varied significantly, ranging from 9.1% in the SERM group to 37.7% in the ZOL group (P<0.001). The overall average number of prior denosumab injections was 4.2 times, with MXM and ZOL having the highest averages of 4.6 injections each, although no statistically significant differences were observed across groups (P=0.335). Likewise, no significant differences were observed in serum corrected calcium, phosphorus, or 25(OH)D levels. However, BMD measurements of the lumbar spine, femoral neck, and total hip significantly varied across groups (P<0.001 for all). In particular, the ZOL group exhibited lower BMD at all measured sites compared to the other groups. At the time of denosumab discontinuation, mean T-scores in all groups were in the range of osteopenia, with the lowest T-scores observed in the ZOL group at the lumbar spine (–2.0±1.0), femoral neck (–2.1±0.8), and total hip (–1.7±0.8).
BMD changes during the 12-month sequential therapy phase: BMD changes during the 12-month sequential therapy period following denosumab discontinuation are presented in Fig. 2. For the lumbar spine, a significant decrease in BMD was observed at 12 months in the IBN and SERM groups compared to that at the time of denosumab withdrawal (–3.5%±2.9% and –3.6%±3.7%, respectively; P<0.05). While a decline in lumbar spine BMD was observed in other treatment groups, these changes were not statistically significant (Fig. 2A). For the femoral neck, the greatest decrease in BMD was observed in the SERM group (–4.0%±2.5%, P<0.05), and significant reductions were also reported in the RIS and IBN groups when compared to baseline measurements. In contrast, the MXM, ALD, and ZOL groups showed slight declines in BMD, which were not statistically significant (Fig. 2B). For the total hip, BMD changes were similar to those observed at the femoral neck. The most pronounced BMD reduction was observed in the SERM group (–3.9%±3.1%, P<0.05), which was followed by the IBN group (–2.2%±1.6%, P<0.076). Total hip BMD reductions were also observed in the MXM, ALD, and ZOL groups, but these changes were not statistically significant (Fig. 2C).; BMD changes after 12 months of sequential treatment were analyzed by dividing the patients into two groups based denosumab treatment duration: those who received <5 injections (approximately 2.5 years) and those who received ≥5 injections (Fig. 3). Generally, patients who received ≥5 denosumab doses experienced a more significant decline in BMD during the 12-month follow-up period compared to those who received <5 doses. In the RIS group, patients who transitioned after ≥5 doses demonstrated more significant BMD changes of the total hip compared to those who received <5 doses (–3.6%±2.7% vs. –1.9%±2.2%). Similarly, in the SERM group, BMD reductions in the lumbar spine and femoral neck were significantly greater in patients who received ≥5 doses than those who received <5 doses (Fig. 3).
BMD changes during the 24-month sequential therapy phase: An additional analysis was conducted to assess BMD changes during the 24-month period following sequential treatment initiation (Fig. 4). This analysis included a limited number of participants who were available for evaluation at 24 months: 21 in the MXM group, 11 in the ALD group, eight in the RIS group, 10 in the IBN group, 22 in the ZOL group, and 11 in the SERM group. Among them, the SERM group exhibited significant BMD reductions at all measured sites 24 months following treatment initiation. The lumbar spine showed the greatest reduction (–6.1%±3.8%), followed by the femoral neck (–3.9%±5.1%) and total hip (– 4.2%±2.9%) (Fig. 4). In the IBN group, only total hip BMD demonstrated a significant decline at 24 months (–3.2%±3.6%, P<0.05) (Fig. 4C). Conversely, the MXM group exhibited a non-significant increase in lumbar spine BMD (0.1%±2.9%) when compared to that at baseline (Fig. 4A). Furthermore, the ZOL group showed a non-significant increase in total hip BMD at 24 months (0.5%±2.1%, P=0.442) (Fig. 4C).
Bone turnover marker during the sequential therapy phase: CTx levels measured 6 months after the last denosumab injection were compared with those observed during the subsequent 12-month treatment period (Table 2). Data from 128 participants out of the total 360 study subjects were analyzed, including 21 from the MXM group, 19 from the ALD group, four from the RIS group, 10 from the IBN group, 48 from the ZOL group, and 26 from the SERM group. A statistically significant 33.4% increase in CTx levels was observed in the SERM group after 12 months of sequential therapy following denosumab withdrawal. Other groups demonstrated increases in CTx levels during the sequential therapy phase, with percentage changes ranging from 10.2% to 13.9%; however, these changes were not statistically significant.
Fracture incidence during the sequential therapy phase: Fracture occurrences observed during the 12-month sequential therapy period are summarized in Table 3. A total of 12 fractures were reported, comprising nine vertebral fractures, two cases of multiple vertebral fractures, and one nonvertebral fracture. The overall fracture incidence was 3.3%, suggesting a low rate of occurrence. The nonvertebral fracture, a wrist fracture, occurred in the RIS group. Among the vertebral fractures, two cases were observed in the MXM group, three cases in the ALD group, and four cases in the ZOL group. A single vertebral fracture was reported in both the IBN and SERM groups. Regarding multiple vertebral fractures, one case was reported in both the ALD and ZOL groups. No statistically significant differences in fracture rates were observed across groups (P=0.545).

DISCUSSION

This retrospective study demonstrated that BMD changes following denosumab discontinuation significantly varied depending on the subsequent anti-resorptive therapy. Regardless of which agent was used, patients who received ≥5 denosumab generally experienced a greater decline in BMD during the follow-up period. Among the follow-up treatments, MXM, ALD, and ZOL were more effective in mitigating BMD loss, whereas RIS, IBN, and SERM were less effective. Despite these variations in BMD changes, no significant differences in fracture incidence was observed across groups during the sequential therapy period.

Given the concerns regarding decreased BMD and increased fracture risk following denosumab discontinuation, clinical guidelines recommend transitioning to alternative anti-resorptive therapies [6,7,24,25]. Despite limited clinical evidence, it is recommended to administer oral bisphosphonates for 12–24 months or ZOL for 1–2 years in patients treated with denosumab for <2.5 years, while ZOL is preferred for those treated for >2.5 years or have a high fracture risk [17,26]. In cases where ZOL is unavailable or contraindicated, oral bisphosphonates are the next best alternative [17]. However, evidence regarding which specific bisphosphonate formulation is most effective after denosumab discontinuation is lacking.

Bisphosphonates differ in their chemical structure, leading to variations in their bone affinity and ability to inhibit farnesyl pyrophosphate synthase [27]. Despite similarities in their BMD increasing effects, their fracture prevention efficacies are different. In particular, IBN, has limited evidence supporting its efficacy in preventing hip or nonvertebral fractures compared to ALD or RIS [24]. This uncertainty complicates the decision-making regarding bisphosphonate use after denosumab discontinuation. Among oral bisphosphonates, ALD has the most robust evidence for its post-denosumab efficacy. The Denosumab Adherence Preference Satisfaction (DAPS) study, a 24-month randomized trial involving 250 postmenopausal women, reported that 1 year of post-denosumab ALD therapy maintained BMD gains achieved by 1 year of denosumab administration [28]. Other observational studies have shown similar effects with ALD, although these studies often involved small patient cohorts. A recent retrospective analysis involving 121 patients reported that BMD loss was effectively mitigated among 34 patients who received post-denosumab ALD therapy [18]. On the other hand, evidence for RIS or IBN after denosumab treatment remains limited, with recent studies indicating that RIS may not prevent BMD loss as effectively as ALD [29,30]. Data on the effects of IBN administration following denosumab treatment are even more scarce. Consistent with previous studies, our findings confirmed that ALD and ZOL administered following denosumab discontinuation mitigated BMD loss. Conversely, RIS, IBN, and SERM were less effective in preventing BMD loss, with SERM demonstrating the greatest decline in BMD among the anti-resorptive agents, similar to previous findings [31,32]. These results may be attributed to the relatively lower bone affinity of RIS and IBN compared to ALD and ZOL [32-34]. However, there was no difference in fracture incidence during the 24-month treatment period across groups. Further research is necessary to determine how differences in BMD reduction between medications may affect long-term fracture risk.

Interestingly, many patients in our study received MXM for the sequential therapy phase. Previous reports have shown that this combination is clinically effective treating osteoporosis [35-39]. The enteric-coated formulation allows for administration without the typical inconveniences associated with bisphosphonates, such as the need for fasting or large water intake, making it more convenient and well-tolerated for Korean patients [38,40]. Its combination with calcitriol, an active form of vitamin D, also provides further bone-preserving benefits for osteoporosis management due to its ability to reduce bone loss and improve bone quality [41-43]. In this study, formulations containing calcitriol may have partially contributed to mitigating bone loss following denosumab discontinuation, potentially reflecting the pharmacological effects of calcitriol. Although the present study did not assess medication adherence, as identified in previous literature, the high adherence to the enteric-coated MXM formulation and its synergistic effects may have contributed to effectively mitigating BMD loss and preventing fractures after denosumab discontinuation, even at a low dose of ALD. While hypercalcemia is a potential concern with calcitriol use, no such cases were reported in the MXM group, with the baseline value of 9.4 mg/dL remaining unchanged at 12 months.

Despite the valuable insights provided by the study, several limitations must be acknowledged. First, due to its retrospective nature, it was not possible to control for confounding factors that could influence bone metabolism, including medication adherence and lifestyle factors (e.g., physical activity). Adherence to medication is particularly important as it significantly impacts drug response, and even within the same class of bisphosphonates, adherence can vary depending on the dosing regimen. However, due to the inherent limitations of a retrospective analysis, assessing medication adherence was not possible in this study, which represents a significant limitation of the research. Second, although this study captures real-world treatment patterns, the quality of evidence is lower compared to prospective randomized controlled trials. Third, the selection bias in medication choice is a potential limitation, as the selection of anti-resorptive agents was based on mutual agreement between the patient and clinician. In our study, the ZOL group presented with a higher prevalence of prior fractures and the lowest BMD at the time of denosumab discontinuation. Likewise, clinicians may have selected more potent agents for patients deemed more vulnerable, potentially leading to selection bias. This limitation, inherent to the retrospective analysis, could be mitigated in future research through prospective studies with standardized protocols for medication selection following denosumab discontinuation. The use of different densitometry devices across institutions is another limitation of this study. Although validated and widely cited conversion formulas were used to standardize values between devices, complete measurement uniformity remains limited compared to using a single device. Lastly, in the retrospective analysis of real-world clinical data, there were instances where the necessary blood test results were not available within the required timeline. While blood test results obtained within a 6-month window before or after the target timeframe were analyzed, certain time-sensitive variables, such as bone turnover markers, were only partially analyzed. As bone turnover markers are highly sensitive to the timing of collection, variability across institutions further limited the reliability of these data. This represents a key limitation of the retrospective design, which restricted a detailed analysis of these markers. Future prospective studies with standardized measurement protocols are essential to address this issue and provide more reliable insights.

Regardless of these limitations, the study has several strengths. First, the study provides a direct comparison of different medications rather than categorizing bisphosphonates as one group, allowing for a more nuanced understanding of each drug’s effects. Second, its multicenter study design involving five major tertiary care centers in Korea are another strength, improving the generalizability of the findings. Moreover, the number of patients in this study is one of the largest among retrospective studies examining post-denosumab treatment efficacy, which provides valuable insights from a real-world dataset that focus on an Asian population. Lastly, a particular strength of this study is the inclusion of MXM and IBN, both of which have been rarely reported in previous studies.

In conclusion, this multicenter, retrospective, real-world analysis of anti-resorptive agents for sequential post-denosumab therapy demonstrates that varying impact of these agents on BMD. Notably, MXM showed comparable effects in mitigating BMD loss when compared to conventional doses of ALD or ZOL. Furthermore, for certain agents, a longer duration of denosumab treatment was associated with a more significant BMD decline during follow-up therapy, emphasizing the need for clinical caution during management. These findings may aid clinicians in selecting appropriate anti-resorptive therapies after denosumab, especially for oral bisphosphonates. However, the limitations of this study must be considered when interpreting these results.

Article information

CONFLICTS OF INTEREST

Yoon-Sok Chung served on the Advisory Board for the SB 16 Denosumab biosimilar (Samsung Bioepis via Ajou University) and the Data Safety Monitoring Board for the Denosumab biosimilar (Celltrion). He received research grants from Samsung Bioepis (SB 16 Denosumab biosimilar, Clinical Trial) and Yuyu Pharma (Maxmarvil after denosumab, Retrospective Analysis), as well as lecture honoraria from Yuyu Pharma (Alendronate), Amgen (Denosumab), Daewoong Pharmaceutical (Zoledronate), Jeil Pharmaceutical (Ibandronate), Dong-A ST (Risedronate), Hanlim Pharma (Risedronate), Handok (Bazedoxifene), Hanmi Pharm (Raloxifene), and Alvogen (Raloxifene). Hyo-Jeong Kim received research grants from Yuyu Pharma (Maxmarvil after denosumab, Retrospective Analysis) and lecture honoraria from Yuyu Pharma (Alendronate) and Amgen (Denosumab). Jeonghoon Ha received research grants from Samsung Bioepis (SB 16 Denosumab biosimilar, Clinical Trial) and lecture honoraria from Amgen (Denosumab), Yuyu Pharma (Alendronate), Organon (Alendronate), DongKook Pharmaceutical (Alendronate), Daewoong Pharmaceutical (Zoledronate), Jeil Pharmaceutical (Ibandronate), Dong-A ST (Risedronate), Handok (Bazedoxifene), Hanmi Pharm (Raloxifene), Alvogen (Raloxifene), and Yuhan (Raloxifene). Seong Hee Ahn participated in a randomized controlled trial sponsored by DongKook (Alendronate). The other authors declare no conflicts of interest.

This study received funding from Yuyu Pharma, Inc. to cover the costs of the analysis; however, it was conducted as an investigator-initiated trial. In line with the researchers’ ethical standards, there were no discussions with the funding provider regarding the study results.

AUTHOR CONTRIBUTIONS

Conception or design: J.H., K.Y.J., K.J.K., S.H.A., H.J.K., Y.S.C. Acquisition, analysis, or interpretation of data: J.H., K.Y.J., K.J.K., S.H.A., H.J.K., Y.S.C. Drafting the work or revising: J.H., K.Y.J. Final approval of the manuscript: H.J.K., Y.S.C.

Acknowledgements

We extend our gratitude to the members of the MAXCARE Study Group for their unwavering commitment and significant contributions to the advancement of the group.

Fig. 1.

The study groups and flow of the study. SERM, selective estrogen receptor modulator; BMD, bone mineral density.

Fig. 2.

Percentage changes in bone mineral density (BMD) at the (A) lumbar spine, (B) femoral neck, and (C) total hip over a 12-month period following the initiation of sequential treatment after denosumab withdrawal. Group comparisons for percentage changes in BMD were adjusted for prior fracture history and baseline BMD using analysis of covariance (ANCOVA). MXM, low-dose alendronate/calcitriol; ALD, full-dose alendronate; RIS, risedronate; IBN, ibandronate; ZOL, zoledronic acid; SERM, selective estrogen receptor modulator. ^aP<0.05 compared with baseline, defined as the time of sequential treatment initiation.

Fig. 3.

Percentage changes in bone mineral density (BMD) over the 12-month period following sequential treatment initiation after denosumab withdrawal, with subgroup analysis based on the number of denosumab injections (<5 vs. ≥5 injections over 2.5 years). Group comparisons for percentage changes in BMD were adjusted for prior fracture history and baseline BMD using analysis of covariance (ANCOVA). Subgroup sizes: (A) low-dose alendronate/calcitriol (MXM; <5, n=65; ≥5, n=53), (B) full-dose alendronate (ALD; <5, n=32; ≥5, n=21), (C) risedronate (RIS; <5, n=12; ≥5, n=8), (D) ibandronate (IBN; <5, n=18; ≥5, n=12), (E) zoledronic acid (ZOL; <5, n=57; ≥5, n=49), and (F) selective estrogen receptor modulator (SERM; <5, n=22; ≥5, n=11). LS, lumbar spine; FN, femoral neck; TH, total hip. ^aP<0.05 compared with baseline, defined as the time of sequential treatment initiation.

Fig. 4.

Percentage changes in bone mineral density (BMD) at the (A) lumbar spine, (B) femoral neck, and (C) total hip over a 24-month period following sequential treatment initiation after denosumab withdrawal. This analysis included participants who were available for evaluation up to 24 months: low-dose alendronate/calcitriol (MXM; n=21), full-dose alendronate (ALD; n=11), risedronate (RIS; n=8), ibandronate (IBN; n=10), zoledronic acid (ZOL; n=22), and selective estrogen receptor modulator (SERM; n=11). Group comparisons for percentage changes in BMD were adjusted for prior fracture history and baseline BMD using analysis of covariance (ANCOVA). ^aP<0.05 compared with baseline, defined as the time of sequential treatment initiation.

Table 1.

Baseline Characteristics of the Study Population at the Initiation of Sequential Treatment after Denosumab Withdrawal

Characteristic	MXM (n=118)	ALD (n=53)	RIS (n=20)	IBN (n=30)	ZOL (n=106)	SERM (n=33)	P value
Age, yr	66.4±8.7	65.8±9.4	68.7±8.8	66.8±7.6	69.0±9.3	67.8±6.8	0.198
Female sex	110 (93.2)	50 (94.3)	19 (95.0)	30 (100.0)	100 (94.3)	33 (100.0)	0.152
BMI, kg/m²	23.5±3.0	23.3±3.2	24.2±4.9	24.0±3.9	23.8±3.6	22.0±3.1	0.116
Comorbidity							0.154
Diabetes	8 (6.8)	4 (7.5)	1 (5.0)	2 (6.7)	8 (7.5)	2 (6.1)
Rheumatoid arthritis	3 (2.5)	2 (3.8)	0	0	3 (2.8)	1 (3.0)
Alcohol	6 (5.1)	3 (5.7)	1 (5.0)	1 (3.3)	5 (4.7)	3 (9.1)	0.056
Prior any fracture	20 (16.9)	18 (34.0)	7 (35.0)	4 (13.3)	40 (37.7)	3 (9.1)	<0.001
Number of denosumab injection, times	4.6±2.4	4.1±1.9	3.9±1.8	4.3±2.0	4.6±2.0	3.9±1.9	0.335
Serum corrected calcium, mg/dL	9.4±0.4	9.3±0.4	9.3±0.4	9.2±0.3	9.5±0.5	9.3±0.4	0.145
Serum phosphorous, mg/dL	3.7±0.5	3.5±0.5	3.5±0.7	3.9±0.5	3.6±0.9	3.6±0.5	0.057
Serum 25-hydroxyvitamin D, ng/mL	35.1±11.1	33.6±9.1	32.0±8.8	31.1±9.3	36.3±6.4	40.5±10.9	0.274
GFR, mL/min/1.73 m²	87.2±10.9	81.6±16.3	89.3±10.1	82.3±11.2	83.6±7.8	85.9±15.7	0.485
BMD, g/cm²
Lumbar spine	0.905±0.096	0.888±0.090	0.892±0.138	0.879±0.085	0.834±0.111	0.848±0.072	<0.001
Femoral neck	0.707±0.098	0.730±0.092	0.675±0.088	0.710±0.105	0.613±0.103	0.638±0.108	<0.001
Total hip	0.787±0.098	0.782±0.103	0.780±0.072	0.790±0.094	0.678±0.238	0.730±0.089	<0.001
T-score
Lumbar spine	–1.8±0.8	–1.9±0.8	–1.8±1.0	–1.9±0.7	–2.0±1.0	–2.0±0.5	0.182
Femoral neck	–1.7±0.7	–1.7±0.7	–1.9±0.6	–1.7±0.8	–2.1±0.8	–1.9±0.6	0.058
Total hip	–1.4±0.8	–1.5±0.8	–1.5±0.6	–1.4±0.8	–1.7±0.8	–1.6±0.8	0.229

Values are expressed as mean±standard deviation or number (%).

MXM, low-dose alendronate/calcitriol; ALD, full-dose alendronate; RIS, risedronate; IBN, ibandronate; ZOL, zoledronic acid; SERM, selective estrogen receptor modulator; BMI, body mass index; GFR, glomerular filtration rate; BMD, bone mineral density.

Table 2.

Changes in CTx Levels during Sequential Therapy Following Denosumab Withdrawal

Group^a	6 months after last denosumab injection	After 12 months of sequential therapy	Percentage changes, %	P value
MXM	0.312±0.131	0.353±0.207	13.1	0.182
ALD	0.268±0.130	0.297±0.137	10.2	0.507
RIS	0.343±0.138	0.381±0.202	11.1	0.208
IBN	0.397±0.281	0.452±0.174	13.9	0.053
ZOL	0.323±0.197	0.362±0.177	12.1	0.156
SERM	0.336±0.395	0.435±0.341	29.5	0.021

Values are expressed as mean±standard deviation.

CTx, crosslinked C-telopeptide of type I collagen (ng/mL); MXM, low-dose alendronate/calcitriol; ALD, full-dose alendronate; RIS, risedronate; IBN, ibandronate; ZOL, zoledronic acid; SERM, selective estrogen receptor modulator

^a Subgroup sizes: MXM (n=21), ALD (n=19), RIS (n=4), IBN (n=10), ZOL (n=48), and SERM (n=26).

Table 3.

Types and Incidence of Fractures Occurring during the Sequential Therapy Following Denosumab Withdrawal

Variable	Total (n=360)	MXM (n=118)	ALD (n=53)	RIS (n=20)	IBN (n=30)	ZOL (n=106)	SERM (n=33)	P value
Fracture incidence	12 (3.3)	2 (1.7)	3 (5.7)	1 (5.0)	1 (3.3)	4 (3.8)	1 (3.0)	0.545
Vertebral fracture	9	2	2	0	1	3	1
Multiple vertebral fracture	2	0	1	0	0	1	0
Nonvertebral fracture (site)	1	0	0	1 (wrist)	0	0	0

Values are expressed as number (%).

MXM, low-dose alendronate/calcitriol; ALD, full-dose alendronate; RIS, risedronate; IBN, ibandronate; ZOL, zoledronic acid; SERM, selective estrogen receptor modulator.

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Effects of Sequential Anti-Resorptive Agents on Bone Mineral Density Following Denosumab Withdrawal: A Multicenter Real-World Study in Korea (MAXCARE Study)

DOI: https://doi.org/10.3803/EnM.2024.2227

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Effects of Sequential Anti-Resorptive Agents on Bone Mineral Density Following Denosumab Withdrawal: A Multicenter Real-World Study in Korea (MAXCARE Study)

Fig. 1. The study groups and flow of the study. SERM, selective estrogen receptor modulator; BMD, bone mineral density.

Fig. 2. Percentage changes in bone mineral density (BMD) at the (A) lumbar spine, (B) femoral neck, and (C) total hip over a 12-month period following the initiation of sequential treatment after denosumab withdrawal. Group comparisons for percentage changes in BMD were adjusted for prior fracture history and baseline BMD using analysis of covariance (ANCOVA). MXM, low-dose alendronate/calcitriol; ALD, full-dose alendronate; RIS, risedronate; IBN, ibandronate; ZOL, zoledronic acid; SERM, selective estrogen receptor modulator. aP<0.05 compared with baseline, defined as the time of sequential treatment initiation.

Fig. 3. Percentage changes in bone mineral density (BMD) over the 12-month period following sequential treatment initiation after denosumab withdrawal, with subgroup analysis based on the number of denosumab injections (<5 vs. ≥5 injections over 2.5 years). Group comparisons for percentage changes in BMD were adjusted for prior fracture history and baseline BMD using analysis of covariance (ANCOVA). Subgroup sizes: (A) low-dose alendronate/calcitriol (MXM; <5, n=65; ≥5, n=53), (B) full-dose alendronate (ALD; <5, n=32; ≥5, n=21), (C) risedronate (RIS; <5, n=12; ≥5, n=8), (D) ibandronate (IBN; <5, n=18; ≥5, n=12), (E) zoledronic acid (ZOL; <5, n=57; ≥5, n=49), and (F) selective estrogen receptor modulator (SERM; <5, n=22; ≥5, n=11). LS, lumbar spine; FN, femoral neck; TH, total hip. aP<0.05 compared with baseline, defined as the time of sequential treatment initiation.

Fig. 4. Percentage changes in bone mineral density (BMD) at the (A) lumbar spine, (B) femoral neck, and (C) total hip over a 24-month period following sequential treatment initiation after denosumab withdrawal. This analysis included participants who were available for evaluation up to 24 months: low-dose alendronate/calcitriol (MXM; n=21), full-dose alendronate (ALD; n=11), risedronate (RIS; n=8), ibandronate (IBN; n=10), zoledronic acid (ZOL; n=22), and selective estrogen receptor modulator (SERM; n=11). Group comparisons for percentage changes in BMD were adjusted for prior fracture history and baseline BMD using analysis of covariance (ANCOVA). aP<0.05 compared with baseline, defined as the time of sequential treatment initiation.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Effects of Sequential Anti-Resorptive Agents on Bone Mineral Density Following Denosumab Withdrawal: A Multicenter Real-World Study in Korea (MAXCARE Study)

Characteristic	MXM (n=118)	ALD (n=53)	RIS (n=20)	IBN (n=30)	ZOL (n=106)	SERM (n=33)	P value
Age, yr	66.4±8.7	65.8±9.4	68.7±8.8	66.8±7.6	69.0±9.3	67.8±6.8	0.198
Female sex	110 (93.2)	50 (94.3)	19 (95.0)	30 (100.0)	100 (94.3)	33 (100.0)	0.152
BMI, kg/m²	23.5±3.0	23.3±3.2	24.2±4.9	24.0±3.9	23.8±3.6	22.0±3.1	0.116
Comorbidity							0.154
Diabetes	8 (6.8)	4 (7.5)	1 (5.0)	2 (6.7)	8 (7.5)	2 (6.1)
Rheumatoid arthritis	3 (2.5)	2 (3.8)	0	0	3 (2.8)	1 (3.0)
Alcohol	6 (5.1)	3 (5.7)	1 (5.0)	1 (3.3)	5 (4.7)	3 (9.1)	0.056
Prior any fracture	20 (16.9)	18 (34.0)	7 (35.0)	4 (13.3)	40 (37.7)	3 (9.1)	<0.001
Number of denosumab injection, times	4.6±2.4	4.1±1.9	3.9±1.8	4.3±2.0	4.6±2.0	3.9±1.9	0.335
Serum corrected calcium, mg/dL	9.4±0.4	9.3±0.4	9.3±0.4	9.2±0.3	9.5±0.5	9.3±0.4	0.145
Serum phosphorous, mg/dL	3.7±0.5	3.5±0.5	3.5±0.7	3.9±0.5	3.6±0.9	3.6±0.5	0.057
Serum 25-hydroxyvitamin D, ng/mL	35.1±11.1	33.6±9.1	32.0±8.8	31.1±9.3	36.3±6.4	40.5±10.9	0.274
GFR, mL/min/1.73 m²	87.2±10.9	81.6±16.3	89.3±10.1	82.3±11.2	83.6±7.8	85.9±15.7	0.485
BMD, g/cm²
Lumbar spine	0.905±0.096	0.888±0.090	0.892±0.138	0.879±0.085	0.834±0.111	0.848±0.072	<0.001
Femoral neck	0.707±0.098	0.730±0.092	0.675±0.088	0.710±0.105	0.613±0.103	0.638±0.108	<0.001
Total hip	0.787±0.098	0.782±0.103	0.780±0.072	0.790±0.094	0.678±0.238	0.730±0.089	<0.001
T-score
Lumbar spine	–1.8±0.8	–1.9±0.8	–1.8±1.0	–1.9±0.7	–2.0±1.0	–2.0±0.5	0.182
Femoral neck	–1.7±0.7	–1.7±0.7	–1.9±0.6	–1.7±0.8	–2.1±0.8	–1.9±0.6	0.058
Total hip	–1.4±0.8	–1.5±0.8	–1.5±0.6	–1.4±0.8	–1.7±0.8	–1.6±0.8	0.229

Group^a	6 months after last denosumab injection	After 12 months of sequential therapy	Percentage changes, %	P value
MXM	0.312±0.131	0.353±0.207	13.1	0.182
ALD	0.268±0.130	0.297±0.137	10.2	0.507
RIS	0.343±0.138	0.381±0.202	11.1	0.208
IBN	0.397±0.281	0.452±0.174	13.9	0.053
ZOL	0.323±0.197	0.362±0.177	12.1	0.156
SERM	0.336±0.395	0.435±0.341	29.5	0.021

Variable	Total (n=360)	MXM (n=118)	ALD (n=53)	RIS (n=20)	IBN (n=30)	ZOL (n=106)	SERM (n=33)	P value
Fracture incidence	12 (3.3)	2 (1.7)	3 (5.7)	1 (5.0)	1 (3.3)	4 (3.8)	1 (3.0)	0.545
Vertebral fracture	9	2	2	0	1	3	1
Multiple vertebral fracture	2	0	1	0	0	1	0
Nonvertebral fracture (site)	1	0	0	1 (wrist)	0	0	0

Table 1. Baseline Characteristics of the Study Population at the Initiation of Sequential Treatment after Denosumab Withdrawal

Values are expressed as mean±standard deviation or number (%).

Table 2. Changes in CTx Levels during Sequential Therapy Following Denosumab Withdrawal

Values are expressed as mean±standard deviation.

Subgroup sizes: MXM (n=21), ALD (n=19), RIS (n=4), IBN (n=10), ZOL (n=48), and SERM (n=26).

Table 3. Types and Incidence of Fractures Occurring during the Sequential Therapy Following Denosumab Withdrawal

Values are expressed as number (%).

MXM, low-dose alendronate/calcitriol; ALD, full-dose alendronate; RIS, risedronate; IBN, ibandronate; ZOL, zoledronic acid; SERM, selective estrogen receptor modulator.

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